Base Composition for Tape Agent

ABSTRACT

The present invention provides a composition for a non-aqueous patch preparation having an excellent adhesibility which can sustainedly release a drug. The patch preparation of the present invention can improve the adhesibility thereof as well as the release property of a drug by the addition of powder ingredient (e.g. a filler). As a result, the long-time sustention of the adhesibility of patch preparations can achieve the improvement of the transdermal absorbability and the sustained release of a drug. By the use of a composition for a patch preparation comprising this powder ingredient, a drug, regardless of the type of a drug is dissolved in an organic solvent or an ionic liquid to prepare a drug solution comprising the organic solvent, the drug solution is incorporated into the non-aqueous patch preparation of the present invention, and thereby a preparation with the improved transdermal-absorbability and sustained release can prepared.

TECHNICAL FIELD

The present invention relates to a composition for a plaster basematerial comprising a filler. Particularly, the present inventionrelates to a composition for a plaster base material in a non-aqueoustape preparation prepared by solvent method.

BACKGROUND ART

In order to prepare a composition for a patch preparation comprising adrug, a set of processes of dissolving a drug in a solvent such as anorganic solvent, diluting the drug solution with a volatile solvent suchas toluene and hexane which is easily evaporated, mixing the solutionwith an adhesive, extending the mixture product, and evaporating thevolatile solvent to prepare a composition for a patch preparation(solvent method) have been typically used. In such case, the organicsolvent used therein has been employed for serving as a transdermalabsorption promoter as well as for dissolving a drug.

However, when a large volume of an organic solvent is used fordissolving a drug, the organic solvent can soften an adhesive layer in atape preparation. As a result, the adhesibility of the tape preparationcan be decreased, and also a part of an adhesive used in the adhesivelayer can remain on the skin when the tape preparation is removed fromthe skin. In order to prevent such trouble caused by using a largevolume of organic solvent, fillers are added to an adhesive to improvethe lowered adhesibility (e.g. Patent Document 1).

Recently, some attempts to use a fatty acid-based ionic liquid as asolution for dissolving a drug or a transdermal absorption promoter havebeen made (e.g. Patent Document 2). However, a plaster base materialused in a tape preparation is a SIS-based lipophilic plaster basematerial which has less affinity for a fatty acid based-ionic liquidbecause a fatty acid based-ionic liquid is in a salt form with highpolarity, and thus such plaster base material has a tendency to be lessmiscible with the ionic liquid. As a result, a drug solution in which adrug is dissolved mainly in a fatty acid based-ionic liquid has atendency to be easily separated from a lipophilic plaster base material.

Although a variety of means for solving these problems have been studieduntil now, drastic means have not been found.

PRIOR ART DOCUMENTS Patent Documents

Patent Document 1: JP 07-215850

Patent Document 2: JP 2009-066457

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

An object of the present invention is to provide a novel lipophilicplaster base material (adhesive layer) prepared by using a filler thatis insoluble both in the adhesive layer and in an organic solvent,wherein the filler is dispersed, and spaces (voids) are formed betweenthe plaster base material and the filler or spaces (voids) are formedbetween the fillers. Furthermore, an object of the present invention isto provide a plaster base material (adhesive layer) for a non-aqueoustape preparation which retains a drug solution comprising an activepharmaceutical ingredient in the spaces (voids) formed by the fillers,and thereby improves the adhesibility of the tape preparation and therelease property of the drug.

Means for Solving the Problems

The present inventors have found that by the addition of a filler(powder) to a non-aqueous patch preparation (tape preparation)containing a conventional fatty acid-based ionic liquid, thesustained-release property of a drug solution can be produced along withthe improvement of the adhesibility of an adhesive layer(PCT/JP2013/66765). Furthermore, the present inventors have studied thematerial quality of the filler (powder) to be added and the amountthereof as well as a combination of the fillers and the compositionthereof, and thus the following findings can be produced.

a) The present inventors have found that, in order to form spaces(voids) between fillers (powder) for retaining a solvent in a plasterbase material (adhesive layer), it is necessary to add an approximateamount of the powder on the basis of the weight of the plaster basematerial (adhesive layer) as shown in the following inequality, whichcan be an index of the bulk density of the powder.

0.2×(the weight of the adhesive layer)×(the bulk density of thepowder)≤the amount of the powder to be added≤0.6×(the weight of theadhesive layer)×(the tap density of the powder)

b) One or more types of powders can be used for forming the spaces(voids) between the fillers (powder). When two or more types of thepowders are combined, it is preferable to use a mixture of powder havinga large particle size and powder having a small particle size. Thepresent inventors have found that the preferred amount of the powderhaving a large particle size (a small bulk density) is 20 to 30%.

c) The spaces (voids) between the fillers (powder) denote the volumewhich can retain a solvent therein. When the practical volume of thesolvent exceeds the approximate amount (volume) thereof as shown in thefollowing inequality, the solvent exudes onto the surface of an adhesivelayer in a tape preparation, and then the adhesibility of the tapepreparation can be decreased.

$\begin{matrix}{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix} < {\frac{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}}{\begin{matrix}{{the}\mspace{14mu} {tap}\mspace{14mu} {density}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix}} \times 1.2}$

d) By making the composition suited as mentioned above, variousnon-aqueous tape preparations containing powder can be prepared, whichcan control two specific properties of the immediate-release andsustained-release properties of a drug as shown in FIG. 13, and thuspreparations having the desired release property can be prepared.

The present inventors have found that even when an ionic liquid or amixture of an ionic liquid and an organic solvent is used in a tapepreparation, a drug solution can be retained in spaces between powder orin spaces between powder and plaster base by adding a lipophilic plasterbase and a powder which is insoluble both in an ionic liquid and in anorganic solvent to a conventional tape preparation, and thereby, toprevent the drug solution from being released from the plaster base. Asa result, the present inventors have found that the drug solution doesnot uselessly exude onto the surface of the tape preparation, and thusthe adhesibility of the tape preparation and the release property of thedrug can be improved. In addition, the present inventors have found thateven when an ionic liquid is encompassed into a lipophilic plaster basematerial (adhesive layer) as droplets, the drug solution can be releasedonto the surface of the plaster base via the spaces between the powderor the spaces between the powder and the plaster base which are formedby the addition of the powder, and thus the release property of the drugcan be improved. The present inventors have completed the presentinvention on the basis of the above findings.

The subject matters of the present invention are as follows.

(1) A composition for a non-aqueous patch preparation comprising a drug,an organic solvent, and a powder which is insoluble both in the organicsolvent and in a lipophilic plaster base material, wherein the powderfor an adhesive layer is contained as shown in the following inequality:

0.2×(the weight of the adhesive layer)×(the bulk density of thepowder)≤the amount of the powder to be added≤0.6×(the weight of theadhesive layer)×(the tap density of the powder).

(2) The composition according to the above item (1), wherein the powderis at least one selected from the group consisting of crystallinecellulose, anhydrous silicic acid, starch, carmellose, carmellose metalsalt, kaolin, agar, carrageenan, pectin, and powdered sugar.(3) The composition according to the above item (1) or (2), wherein thepowder is a mixture of powders.(4) The composition according to the above item (3), wherein the mixturecomprises 20 to 30 w/w % of anhydrous silicic acid.(5) The composition according to any one of the above items (1) to (4),wherein the organic solvent comprises a fatty acid-based ionic liquidand/or a salicylic acid-based ionic liquid.(6) The composition according to the above item (5), wherein the fattyacid-based ionic liquid is an equimolar salt of a saturated orunsaturated fatty acid having 3 to 22 carbon atoms and an alkanolaminehaving 6 to 9 carbon atoms.(7) The composition according to the above item (5) or (6) furthercomprising a saturated or unsaturated fatty acid having 10 to 22 carbonatoms.(8) The composition according to the above item (7), wherein thesaturated or unsaturated fatty acid having 3 to 22 carbon atoms is atleast one selected from the group consisting of lactic acid, levulinicacid, decanoic acid, oleic acid, isostearic acid, and myristic acid.(9) The composition according to the above item (5), wherein thealkanolamine is at least one selected from the group consisting oftriethanolamine, triisopropanolamine, and diisopropanolamine.(10) The composition according to the above item (5), wherein the fattyacid-based ionic liquid and/or the salicylic acid-based ionic liquid areat least one selected from the group consisting of triethanolaminelactate, triisopropanolamine lactate, triethanolamine levulinate,diisopropanolamine levulinate, triisopropanolamine decanoate,triethanolamine salicylate, diisopropanolamine oleate, triethanolamineisostearate, diisopropanolamine isostearate, and diisopropanolaminemyristate.(11) The composition according to any one of the above items (1) to(10), wherein the lipophilic plaster base material comprises anelastomeric styrene-isoprene-styrene block copolymer.(12) The composition according to any one of the above items (1) to(11), wherein the drug is selected from a small molecular medicinalcompound, a protein medicine, an antigen peptide, or a nucleic acidderivative.(13) The composition according to any one of the above items (1) to(12), wherein the organic solvent is contained as shown in the followinginequality:

$\begin{matrix}{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix} < {\frac{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}}{\begin{matrix}{{the}\mspace{14mu} {tap}\mspace{14mu} {density}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix}} \times 1.2}$

(14) The composition according to any one of the above items (1) to (13)further comprising a diester and/or a triester.(15) The composition according to any one of the above items (1) to (14)wherein the diester is at least one selected from the group consistingof diethyl sebacate, diisopropyl adipate, and diisobutyl adipate, andthe triester is at least one selected from the group consisting ofmedium-chain triglyceride and triacetin.

Effects of the Invention

The composition for a non-aqueous patch preparation of the presentinvention relates to a non-aqueous patch preparation (tape preparation)comprising a drug solution in which a drug is dissolved in an organicsolvent (mainly comprising an fatty acid-based ionic liquid), alipophilic plaster base material, and a powder. By the addition ofpowder, the drug solution with high polarity can be retained in thespaces between the powder formed in the lipophilic plaster base materialto avoid releasing the drug solution from the lipophilic plaster basematerial and exuding onto the surface of the plaster base. As a result,the deterioration in the adhesibility of the tape preparation can beprevented. In addition, the release property and utilization rate of adrug can be improved because the routes for releasing the drug solutionout of the plaster base are secured with said spaces.

As described above, the decrease in the adhesibility of a tapepreparation caused by the use of an organic solvent with high polarityfor dissolving a drug (mainly comprising an fatty acid-based ionicliquid), which has been a problem in conventional tape preparations, canbe improved by using powder in a tape preparation, and also the releaseproperty and utilization rate of a drug can be greatly improved. Thus,such long-time sustention of the adhesibility of tape preparations canachieve the improvement of the transdermal absorbability and thesustained release of a drug.

Also, the adhesibility of the lipophilic plaster base material to abacking support body (a backing) can be enhanced by the addition of adiester and/or a triester to the organic solvent, and thus the backingsupport body is not removed from the plaster base material in the tapepreparation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a conceptual diagram showing a cross-section of the plasterbase in the non-aqueous patch preparation (tape preparation) of thepresent invention. FIG. 1 shows that the powder is dispersed into thelipophilic plaster base material (oil-soluble plaster base), and thedrug solution is retained in the spaces between the powder or in thespaces between the powder and the plaster base. Furthermore, FIG. 1shows that quite-narrow channels for releasing the drug solution fromthe inside of the plaster base onto the surface thereof are formed byconnecting these spaces to each other. The parts in which the powder ispresent on the surface of the plaster base cause the exudation of thedrug solution from the spaces around the powder, whereas the parts inwhich the powder is not present on the surface of the plaster base causeless exudation or less release of the drug solution. As a result, thedeterioration of the adhesibility of the patch preparation is preventedas a whole. FIG. 1 also shows the above.

In FIG. 2, the blue pigment (brilliant blue FCF) was dissolved in thesolution of triethanolamine levulinate in macrogol 400 (weight ratio of6:14), light silicic acid as the powder was added thereto, the solutionwas mixed with the lipophilic plaster base material, and then themixture product was extended to prepare the tape preparation followingthe conventional solvent method. The tape preparation was cut into 3×3cm, dipped into a beaker containing 8 mL of purified water, and thenincubated at 32° C. for 6 hours. The emission amount of the blue pigmentfrom the sample was measured by the absorption spectrum measurementmethod at a wavelength of 630 nm. FIG. 2 is a diagram showing thecorrelation between the emission amount of the blue pigment and thevolume ratio of the powder to the plaster base material (the volume ofthe powder/the volume of the lipophilic plaster base material). Thevolume of the powder was calculated based on the bulk density thereof.

FIG. 3 is a diagram showing the correlation between the emission amountof the blue pigment and the volume ratio of the powder to the plasterbase material in a similar measurement method to that of FIG. 2, exceptthat crystalline cellulose is used as the powder.

FIG. 4 is a diagram showing the correlation between the emission amountof the blue pigment and the volume ratio of the powder to the plasterbase material in a similar measurement method to that of FIG. 2, exceptthat corn starch is used as the powder.

FIG. 5 is a diagram showing the same correlation as that of FIG. 2, butthe volume ratio of the powder to the plaster base material iscalculated based on the tap density thereof.

FIG. 6 is a diagram showing the same correlation as that of FIG. 3, butthe volume ratio of the powder to the plaster base material iscalculated based on the tap density thereof.

FIG. 7 is a diagram showing the same data as that of FIG. 2 in which thehorizontal axis represents the amount of the powder in the adhesivelayer of the preparation.

FIG. 7 shows that the amount of light silicic acid is preferably 1 to 5w/w %, and more preferably 2.5 to 5 w/w %.

FIG. 8 is a diagram showing the same data as that of FIG. 3 in which thehorizontal axis represents the amount of the powder in the adhesivelayer of the preparation. FIG. 8 shows that the amount of crystallinecellulose is preferably 2.5 to 18 w/w %, and more preferably 5 to 15 w/w%.

FIG. 9 is a diagram showing the same data as that of FIG. 4 in which thehorizontal axis represents the amount of the powder in the adhesivelayer of the preparation. FIG. 9 shows that the amount of corn starch ispreferably 20 to 42 w/w %, and more preferably 29 to 42 w/w %.

FIG. 10 is a diagram showing that when two types of powders havingdifferent particle sizes are combined and the volume of powder having alarger particle size accounts for about 70% of the total, the volume ofthe mixture of the powders becomes the smallest. FIG. 10 is described inKimio KAWAKITA et al., Bulletin of the Faculty of Engineering, HoseiUniversity 2, pages 47-53.

FIG. 11 is a diagram showing in vivo blood level change of the drug inmice produced by the use of the tape preparation containing powders(Test No. A244). FIG. 11 shows that the tape preparation containing thepowders has the sustained-release property of the drug.

FIG. 12 is a diagram showing the change in the drug blood level in miceproduced by the use of the tape preparation with no powder (Test No.A068). FIG. 12 shows that the drug blood level reaches a peak two hoursafter the preparation was applied to the skin, and then is rapidlydecreased. FIG. 12 shows the change in the drug blood level which isgreatly different from that of FIG. 11.

FIG. 13 is a diagram showing that the change in drug the blood levelover time as shown in FIG. 11, which is composed of biphasic propertiesof the immediate-release and sustained-release properties of the drug.

FIG. 14 is a conceptual diagram showing the imbalance of the powder inthe adhesive layer which is presumed to produce biphasic behaviors asshown in FIG. 13. The result means the presence of the region formingthe spaces (voids) in which the powder is collectively combined in theadhesive layer and the region in which the powder is relatively empty inthe adhesive layer, that is, the region in which the spaces (voids) arenot sufficiently formed.

FIG. 15 is a diagram showing the change in the drug blood level overtime in the rat produced by the use of the preparation of Test No. N423.The sample of the present invention mainly produces theimmediate-release property of the drug.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The term “drug” in the present invention denotes a drug for medical useselected from a small molecular medicinal compound, a protein medicine,an antigen peptide, or a nucleic acid derivative. Many of the drugs usedherein have hydrophilic residue(s) as a main substituent (or drugs in asalt form thereof). Thus, such drugs are less soluble in a lipophilicplaster base material. For such unfavorable insolubility, an ionicliquid with high polarity is used to dissolve the drug, and the solutionof the drug in the ionic liquid is used as a drug solution. Among thedrugs of the present invention, for example, a small molecular medicinalcompound denotes a drug having an acidity (“acidic drug”) or a drughaving a basicity (“basic drug”).

The term “acidic drug” herein denotes a drug which has a carboxylic acidas a functional group and has an acidity as a whole of the compound.Examples of the acidic drug include non-steroid anti-inflammatory drugs(NSAIDs) such as indomethacin, ketoprofen, ibuprofen, flurbiprofen,diclofenac, etodolac, and loxoprofen; anti-allergic drugs such astranilast, cromoglicic acid, and pemirolast; sedative hypnotic drugs oranti-anxiety drugs such as amobarbital, secobarbital, and phenobarbital;and muscle relaxant drugs such as dantrolene, and mivacurium. Preferredexamples of the acidic drug include indomethacin, flurbiprofen,ketoprofen, etodolac, ibuprofen, loxoprofen, and diclofenac.

The term “basic drug” herein denotes a drug which has a primary,secondary, or tertiary amine structure as a functional group and has abasicity as a whole of the compound. Examples of the basic drug includetopical anesthetic drugs such as lidocaine, dibucaine, bupivacaine,procaine, mepivacaine, bupivacaine, and tetracaine; anti-histamine drugssuch as diphenhydramine; analgesic drugs such as tramadol;anti-spasmodic drugs such as eperisone; muscle relaxant drugs such astolperisone; antitussive drugs such as dextromethorphan; acetylcholinedecomposition inhibitors such as donepezil; and opioid analgesic drugssuch as morphine, codeine, naloxone, fentanyl, and oxycodone. Preferredexamples of the basic drug include lidocaine, tolperisone, bupivacaine,eperisone, tramadol, morphine, and donepezil.

The term “protein medicine” herein denotes a protein for medical use.Examples of the protein medicine include various recombinant proteinsand modified proteins which are relatively small molecules. Examples ofvarious recombinant proteins and modified proteins include insulin,human growth hormone, elcatonin, calcitonin, EGF, VEGF, and GLP-1.

The term “antigen peptide” herein denotes an antigenic fragment derivedfrom a foreign microbe or a tumor cell which is used for stimulatingimmunity. Examples of the antigen peptide include WT-1, and humanpapillomavirus.

The term “nucleic derivative” herein denotes a general term for DNA andRNA which are used as a medicinal ingredient. The DNA used herein is notespecially limited as long as it is DNA for gene therapy. Examples ofthe nucleic derivative include DNA vaccine, antisense, ribozyme,aptamer, and siRNA.

The term “fatty acid-based ionic liquid” in the present inventiondenotes a Brønsted salt prepared from a fatty acid having 3 to 22 carbonatoms and a alkanolamine compound having 6 to 9 carbon atoms, which isin a viscous liquid form at ambient temperature.

The term “salicylic acid-based ionic liquid” in the present inventiondenotes a Brønsted salt prepared from salicylic acid and an alkanolaminecompound having 6 to 9 carbon atoms, which is in a viscous liquid format ambient temperature.

Preferably, in order to enhance the skin permeability of a drug, theionic liquid used in a drug solution is in the state that the drugsolubility of the drug solution is close to saturation. Thus, the drugsolubility of the drug solution can be controlled through the additionof one or more saturated or unsaturated fatty acids having 3 to 22carbon atoms or a combination of various fatty acid-based ionic liquids.

The “fatty acid-based ionic liquid and/or salicylic acid-based ionicliquid” in the present invention include an equilibrium mixture of eachequimolar amount of an organic carboxylic acid and an amine compound,besides a Brønsted salt. Preferred examples of the ionic liquid includetriethanolamine lactate, triisopropanolamine lactate, triethanolaminesalicylate, triisopropanolamine salicylate, triisopropanolaminedecanoate, triethanolamine decanoate, diisopropanolamine decanoate,diisopropanolamine oleate, triethanolamine isostearate,diisopropanolamine isostearate, and a mixture thereof.

The term “drug solution” in the present invention denotes a solution inwhich a drug is dissolved in an organic solvent. Also, the drug solutiondenotes a solution further comprising an ionic liquid as a solubilizingagent for the drug or a transdermal absorption accelerator. The drugsolution of the present invention typically comprises an ionic liquidwith high drug solubility. Also, the organic solvent used herein isrequired to be miscible with the ionic liquid. Thus, a polar organicsolvent can be typically used. For example, alcohols such as propyleneglycol and/or esters such as diethyl sebacate and isopropyl myristatecan be used.

The term “powder” in the present invention denotes a solid powderedreagent which is insoluble and immiscible both in a drug solution and ina lipophilic plaster base material (oil-soluble plaster base material).Specifically, the powder is a solid powdered reagent which is insolublein a solvent such as an organic solvent in the drug solution even thoughthe powder swells due to the absorption of the solvent. Examples of thepowder include a solid powdered reagent (filler) used in a plaster basein a patch preparation such as anhydrous silicic acid, crystallinecellulose, zinc oxide, titanium oxide, kaolin, and calcium carbonate.Furthermore, examples of the powder include flour, starch powder such ascorn starch, carmellose, carmellose metal salt, agar, carrageenan,pectin, powdered sugar, polyethylene powder, and polystyrene sulfonate.Preferred examples of the powder include crystalline cellulose,anhydrous silicic acid, starch, carmellose, and carmellose metal salt.The adhesibility of the patch preparation can be improved withincreasing the amount of the powder of the present invention. Whereas,when the powder is excessive in amount, the patch preparation becomeshard, and the adhesibility of the patch preparation is deteriorated.Thus, in order to form spaces (voids) between the powder for retaining asolvent in a plaster base material (adhesive layer), it is necessary toadd the preferred amount of the powder on the basis of the weight of theplaster base material (adhesive layer) as shown in the followinginequality, which can be an index of the bulk density of the powder.

0.2×(the weight of the adhesive layer)×(the bulk density of thepowder)≤the amount of the powder to be added≤0.6×(the weight of theadhesive layer)×(the tap density of the powder).

In addition, one or more types of powders can be used for forming thespaces (voids) between the powders. When two or more types of thepowders are combined, it is preferable to use a mixture of powder havinga large particle size and powder having a small particle size. In suchcase, it is preferable that the amount of the powder having a largeparticle size (i.e., having a small bulk density) is 20 to 30%.

Also, the spaces (voids) between the powder denote the volume which canretain a solvent (drug solution) in a plaster base material (adhesivelayer). The volume is shown in the following inequality. When thepractical amount of an organic solvent to be added exceeds the volume asshown below, the solvent (drug solution) exudes onto the surface of theadhesive layer, and then the adhesibility of the preparation can bedecreased.

$\begin{matrix}{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix} < {\frac{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}}{\begin{matrix}{{the}\mspace{14mu} {tap}\mspace{14mu} {density}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix}} \times 1.2}$

Thus, the immediate-release and sustained-release properties of a drugin a non-aqueous tape preparation containing powder can vary dependingon the changes in the amount and composition of the powder. For example,preparations having a desired release property can be prepared bycontrolling two specific properties of the immediate-release andsustained-release properties of a drug as shown in FIG. 13.

In order to control the immediate-release and sustained-releaseproperties of a drug, the spaces to be formed can be properly controlledby combining various powders having different bulk densities. Forexample, a combination of 20 to 30 w/w % of anhydrous silicic acidhaving a small bulk density, and crystalline cellulose or corn starchhaving a large bulk density may be used as a mixture of powders.

The term “powder which is insoluble both in the drug solution and in thelipophilic plaster base material” in the present invention means that apowder is insoluble both in an organic solvent and an ionic liquid, andinsoluble in a lipophilic plaster base so that the spaces between thepowder formed in the lipophilic plaster base can be retained. The term“insoluble” is used in the sense of insolubility, and means that 1 mg ofpowder cannot be dissolved in 10 g of an organic solvent or a lipophilicplaster base, according to the definition of solubility in the U.S. (theU.S. Pharmacopeia National Formulary).

The term “organic solvent” in the present invention denotes a solventthat is miscible with an ionic liquid, which is used for preparing adrug solution in which a drug is dissolved in combination with the ionicliquid. The organic solvent in the present invention can be also used asa transdermal absorption accelerator. Furthermore, the organic solventcan be also used for dispersing the organic carboxylic acid-based ionicliquid in which a drug is dissolved into the plaster base. Examples ofthe organic solvent in the present invention include alcohols such asethanol, propanol, and oleyl alcohol; polyalcohols such as ethyleneglycol, propylene glycol, 1,3-butanediol, polyethylene glycol(macrogol), and glycerin; and esters such as diethyl sebacate, isopropylmyristate, propylene carbonate, and diisopropyl adipate. In addition,the organic solvent includes fatty acids such as lactic acid, levulinicacid, decanoic acid, oleic acid, myristic acid, and isostearic acid.These organic solvents may be used in suitable combination to achievethe above purposes. More preferably, polyalcohols such as propyleneglycol, 1,3-butanediol, polyethylene glycol, and glycerin can be used incombination with esters such as diethyl sebacate, isopropyl myristate,propylene carbonate, and medium-chain triglyceride.

Among the above organic solvents, the solvent retained in the spaces(voids) formed by powder is mainly a solvent which is hard to dissolvean adhesive layer (lipophilic plaster base material) (e.g. a solventwhich is less compatible with the adhesive layer). Examples of thesolvent which is less compatible with the adhesive layer include analcohol solvent (e.g. macrogol, propylene glycol, and polyethyleneglycol) and a protic solvent such as a fatty acid-based ionic liquid anda fatty acid. On the other hand, an ester solvent (e.g. diethyl sebacateand isopropyl myristate) is more compatible with the adhesive layer(lipophilic plaster base material), and thus it has a tendency to behard to be retained in the spaces (voids) in the adhesive layer. Thus,in studying the volume of the solvent retained in the spaces (voids)formed by the powder to keep the adhesibility of a preparation, thevolume of the solvent which is less compatible with the adhesive layershould be mainly evaluated.

The term “lipophilic plaster base material” in the present inventiondenotes a plaster base (adhesive) comprising a lipophilic polymer as amain component. The plaster base is composed of an elastomer and alipophilic (hydrophobic) adhesive, in which a drug solution is dispersedor emulsified into the plaster base. When the plaster base is composedof an elastomer and a lipophilic (hydrophobic) adhesive, it can be usedas a non-aqueous tape preparation (plaster). When the plaster base iscomposed of an elastomer and a hydrophilic adhesive, it can be used asan aqueous patch preparation (cataplasm). As described above, thelipophilic plaster base material is composed of various reagents such asan elastomer, a tackifier, and a softening filler.

Examples of the elastomer include synthetic rubbers such as astyrene-isoprene-styrene copolymer (SIS), a silicon rubber,polyisobutylene, a polystyrene-butadiene copolymer, and polyisobutylene;acrylic acid resins such as alkyl acrylate and alkyl methacrylate; andnatural rubbers.

The tackifier denotes a reagent which can be added into the elastomersuch as a SIS resin to enhance the adhesibility of a patch preparationto the skin. Examples of the tackifier include a polyterpene resin, apolyolefin resin (e.g. Plastibase®), a polystyrene resin, an aromaticpetroleum resin, rosin, and hydrogenated rosin. Preferred examples ofthe tackifier include a polyterpene resin and a polyolefin resin (e.g.Plastibase®).

The softening agent is a reagent which can be added to make theelastomer such as a SIS resin and the adhesive flexible. Examples of thesoftening agent include petroleum-based softening agents such aspolybutene, polyisobutylene, and process oil; fatty oil-based softeningagents such as palm oil and castor oil; purified lanolin; and liquidparaffin. Preferred examples of the softening agent include polybuteneand liquid paraffin.

The patch preparation of the present invention may further compriseadditives such as an antioxidant, a surfactant, a thickening agent, anda surfactant as long as the effects of the present invention are notprevented. As the suitable additives, commercially available reagentsmay be used for any purpose.

Examples of the antioxidant include organic antioxidants such as BHT,propyl gallate, and sodium ascorbate; and inorganic antioxidants such assodium thiosulfate, sodium bisulfite, sodium sulfite, and sodiumpyrosulfite.

In addition, a thickening agent such as Carbopol®, an ultravioletabsorbing agent, and/or powders may be added.

Examples of the surfactant can include a non-ionic surfactant, ananionic surfactant, a cationic surfactant, and an amphoteric surfactant.Examples of the non-ionic surfactant include sorbitan monolaurate,sorbitan monopalmitate, sorbitan sesquioleate, glycerin monostearate,decaglyceryl monolaurate, hexaglycerin polyricinoleate, polyoxyethylene(9) lauryl ether, polyoxyethylene (2) lauryl ether, polyoxyethylene(4,2) lauryl ether, polyoxyethylene (5) nonylphenyl ether,polyoxyethylene (7,5) nonylphenyl ether, polyoxyethylene (10)nonylphenyl ether, polyoxyethylene (3) octylphenyl ether,polyoxyethylene (10) octylphenyl ether, polyoxyethylene (10) oylelamine,polyoxy (5) oleylamine, polyoxy (5) oleic amide, polyoxyethylene (2)monolaurate, monoglyceride stearate, and polyoxyethylene castor oil(hydrogenated castor oil).

Examples of the anionic surfactant include sodium lauryl sulfate,potassium lauryl sulfate, triethanolamine lauryl sulfate, sodium cetylsulfate, sodium lauroyl sarcosinate, sodium di-2-ethylhexylsulfosuccinate, sodium polyoxyethylene (10) lauryl ether phosphate,sodium polyoxyethylene (4) lauryl ether phosphate, sodiumpolyoxyethylene (5) cetyl ether phosphate, and sodium polyoxyethylene(6) oleyl ether phosphate.

Examples of the cationic surfactant include stearyl trimethylammoniumchloride, distearyl dimethylammonium chloride, benzalkonium chloride,and stearyl dimethyl benzylammonium chloride.

Examples of the amphoteric surfactant include betainelauryldimethylaminoacetate and 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine. Lauroyl diethanolamide may also be used as theamphoteric surfactant.

In addition, a thickening agent such as Carbopol®, an ultravioletabsorbing agent, and/or powders may be added.

The term “patch preparation” in the present invention denotes anon-aqueous patch preparation (tape preparation) which does not containwater as an essential ingredient. As the plaster base in the patchpreparation of the present invention, conventional bases, for example,an acrylic acid resin base, or a base of a SIS resin which containsreagents such as a tackifier and a softening agent can be used.Preferred examples of the base include a base in which a SIS resin isused as an elastomer.

As a method for preparing the patch preparation of the presentinvention, similar methods to those of adhesive tapes may be used.Examples of the method include a solvent-coating method. Thesolvent-coating method is a method which comprises preparing a plasterbase composition comprising a drug (drug solution), and directly coatinga backing support body with the composition followed by drying. Also, amethod can be used which comprises once coating a release paper with theplaster base composition followed by drying, and then removing the paperfollowed by contact-pressing the composition on the paper to thebacking.

The release paper can be used for protecting the adhesive layer. Asexamples of the paper, a polyethylene-coated quality paper, apolyolefin-coated glassine paper, a polyethylene terephthalate(hereinafter referred to as PET) film, a polypropylene film or the like,one side of which is treated with silicon, may be used.

In addition, an additive having a multiple ester such as a diester and atriester can be added into the patch preparation of the presentinvention. The adhesibility of an additive to a backing is decreased bymixing a powder with the additive. The present inventors have studiedthe problem and found that the additive having a multiple ester such asa diester and a triester can enhance the adhesibility of an additive toa backing support body (backing) in a tape preparation, and thus theremoval of the backing in use can be prevented. Examples of the diesterinclude diethyl sebacate, diisopropyl adipate, and diisobutyl adipate.Examples of the triester include medium-chain triglyceride andtriacetin.

EXAMPLES

Hereinafter, the present invention will be described more specificallywith reference to Examples. However, the present invention is notintended to be limited to them by any means.

Example 1

Measurement of the Bulk Density and the Tap Density of Filler (Powder)

(1) Measurement of the Bulk Density of Filler (Powder)

The bulk density of a powder (g/cm³) is a ratio of the mass of thepowder sample in an untapped (loose) state and the volume of the powderincluding the interparticle void volume. Thus, the bulk density of apowder depends on the particle density of the powder and the spatialarray of particles within the powder layer.

a) Method:

The volume of a powder sample with the known mass added into a graduatedcylinder through a sieve was measured to calculate the bulk density ofthe powder. Specifically, a powder was passed through a sieve with 1.0mm or more meshes to crush an aggregate which may be formed duringstorage. About 100 g of a sample (m) was weighed with 0.1% accuracy, andthe sample was carefully added into a dry 250 mL graduated cylinder(minimum scale value: 2 mL) without compaction. The upper surface of thepowder layer is carefully floated without compaction to read the aeratedbulk volume (V) of the powder to minimum scale value. The bulk densityof the powder (g/mL) was calculated according to the formula m/V.

b) Measurement Result:

The measured results of JP corn starch, light anhydrous silicic acid(AEROSIL® 200), and crystalline cellulose (CEOLUS®) are shown in Table 1below.

(2) Measurement of the Tap Density of Filler (Powder)

The tap density of a powder means the increased bulk density of thepowder after a container containing the powder sample is mechanicallytapped. The tap density of a powder is given by mechanically tapping agraduated cylinder or container for measurement containing the powdersample.

a) Method:

The initial volume or mass of powder is measured, and then a graduatedcylinder or container for measurement containing the powder ismechanically tapped until the volume or mass shows little change to readthe volume or mass of the tapped powder. The mechanical tapping isperformed by lifting up the graduated cylinder or container, and thendropping it down a given distance under its own weight. Specifically, a250 mL graduated cylinder (minimum scale value: 2 mL) with a mass of220±44 g and a device for dropping down the graduated cylinder from aheight of 3±2 mm at a tapped rate of 250±15 times/min are used.

In the same manner as the above (1), the bulk volume (V) of the powderis measured. The powder sample to be measured is tapped 10 times, 500times, and 1250 times to read the corresponding bulk volumes V10, V500,and V1250 to the minimum scale value. When the difference between V500and V1250 is less than 2 mL, V1250 is used as the tap volume. When thedifference between V500 and V1250 exceeds 2 mL, tapping is repeated inincrements of 1250 times for each time until the difference betweensucceeding measurements reaches less than 2 mL. The tap density of apowder (g/cm³) is calculated according to the formula m/Vf in which Vfis the final tap volume of the powder.

b) Measurement Result:

The measured results of JP corn starch, light anhydrous silicic acid(AEROSIL® 200), and crystalline cellulose (CEOLUS®) are shown in Table 1below.

TABLE 1 Bulk Density Tap Density AEROSIL ® 200 0.04 0.09 (lightanhydrous silicic acid) CEOLUS ® 0.14 0.31 (crystalline cellulose) JPcorn starch 0.50 0.73

The above bulk density and tap density of each powder mean the volume ofAEROSIL®, CEOLUS®, or corn starch. For example, when 1 g of AEROSIL® 200is used as the powder (filler), the powder occupies a volume of 25 cm³(calculated as the bulk density of the powder). Also, corn starchoccupies a volume of 2 cm³ (calculated as the bulk density of thepowder).

If each specific gravity of AEROSIL®, CEOLUS®, and corn starch is in thesame range, each volume of the powders denote the size of spaces (voids)formed by each powder. For example, it is shown that the spaces (voids)formed by AEROSIL® or CEOLUS® are large in size, whereas the spaces(voids) formed by corn starch is small in size.

When an excessive amount of light anhydrous silicic acid or crystallinecellulose is added to the adhesive layer of a preparation, the adhesivelayer enters spaces (voids) between the powder, and thus the spaces(voids) show little change. On the other hand, when an excessive amountof powder forms spaces (voids) in the adhesive layer of a tapepreparation, the tape preparation becomes hard, and the adhesibility ofthe tape preparation is deteriorated. Thus, when powder is added, it isrequired to optimize the weight ratio of the powder and the adhesivelayer of the preparation. On the other hand, when powder is small inamount, little space (void) is formed, and thus the powder cannotsufficiently exert an effect thereof.

Example 2 Optimization of the Ratio of the Volume of Filler (Powder) andthe Amount of Adhesive Layer (Tape Preparation Base Material)

The problem for effectively utilizing the spaces (voids) formed in thetape preparation base material is to determine the amount of a filler(powder) to be added into the adhesive layer of the preparation.

The amounts of the ingredients in the adhesive layer were maintained atan almost constant rate, and the amount of the powder to be added wasincreased. The amount of the powder to be added for forming spaces(voids) between the powder and releasing the drug solution via thespaces (voids) was investigated. The volume of the powder was calculatedbased on the amount of the powder to be added using the bulk density ofthe powder as shown in Example 1, and the association between thevolumes of the powder and the adhesive layer was evaluated.

As shown in FIG. 1, the spaces (voids) between the powder are formedwith increasing the amount of the powder to be added. As a result, adrug retained in the spaces (voids) is released from the surface of theadhesive layer (lipophilic adhesive plaster base) to the outside thereofvia the spaces (voids). In order to confirm the release property of adrug (i.e., the spaces (voids) formed by the powder), by using brilliantblue FCF as an alternative to the drug, the release property of thepigment from the surface of the adhesive layer (lipophilic adhesiveplaster base) was evaluated.

(1) Preparation of Adhesive Layer (Lipophilic Adhesive Plaster Base)

Each reagent was weighed according to the composition (part by weight)in Table 2 below, and brilliant blue FCF was dissolved in the solutionof triethanolamine levulinate in macrogol 400 (weight ratio of 6:14) toprepare the drug solution. Following the conventional solvent method,terpene resin, styrene-isoprene-styrene copolymer (SIS),butylhydroxytoluene, and liquid paraffin were dissolved in toluene, andthen the macrogol 400 solution (weight ratio 6:14) and light anhydroussilicic acid (AEROSIL® 200) were added thereto and mixed. Next, eachmixture was applied on the silicone-coated PET film and dried. Afterremoval of the toluene, the backing was laminated to prepare the tapepreparations.

(2) Detection of the Release Property of Drug Solution (i.e., Spaces(Voids) Formed by Powder)

The prepared tape preparations were tested on the release property ofbrilliant blue FCF from the adhesive layer. Specifically, the preparedtape preparations were cut into 3×3 cm, dipped into a beaker containing8 mL of purified water, and then incubated at 32° C. for 6 hours. Next,the emission of the blue pigment from each tape preparation of theexample was measured by the absorption spectrum measurement method at awavelength of 630 nm. The results are also shown in Table 2 below.

TABLE 2 A1 A2 A3 A4 A5 A6 A7 A8 Drug Solution: Brilliant blue 0.0160.016 0.016 0.016  0.016 0.016 0.016 0.016 FCF Triethanolamine 10 9.969.92 9.81  9.73 9.62 9.53 9.42 Levulinate/Macro gol 400 Adhesive:Triethanolamine 10 9.96 9.92 9.81  9.73 9.62 9.53 9.42 Levulinate/Macrogol 400 Terpene Resin 38 37.85 37.70 37.26 36.97 36.54 36.22 35.78 SIS20 19.92 19.84 19.61 19.46 19.23 19.06 18.83 Liquid Parffin 17 16.9316.87 16.67 16.54 16.35 16.20 16.01 Butylhydroxytoluene 1 1.00 0.99 0.98 0.97 0.96 0.95 0.94 (Total weight of 96.0 95.6 95.3 94.1 93.4  92.391.5 90.4 adhesive layer) Filler (Powder): AEROSIL ® 0 0.37 0.75 1.862.6 3.7 4.5 5.6 (Volume) (9.3) (18.6) (46.5) (65)  (92.5) (112.5) (140)Volume ratio of 0 9.7 19.5 49.4 69.6  100.2 123.0 154.9 powder toadhesive layer (%) Preparation Form: good good good good good good badbad Emission Amount 0.008 0.019 0.061 0.211  0.211 0.190 0.143 0.219(Absorbance/ Measurement Wavelength 630 nm) [NOTE] The volume ofAEROSIL ® was calculated according to the weight thereof/the bulkdensity thereof. The “volume ratio of the powder to the adhesive layer”was calculated according to the specific gravity of the adhesive layercontaining the drug solution defined as 1.

FIG. 2 is a diagram showing the emission amount of brilliant blue FCF asshown in Table 2. FIG. 2 shows that when the volume of the powder to beadded for the adhesive layer exceeds about 20%, the emission amount ofthe brilliant blue is raised. Also, FIG. 2 shows that when the volume ofthe powder to be added for the adhesive layer exceeds about 50%, theemission amount of the brilliant blue reaches a peak.

As a result, when the volume of the powder to be added for the adhesivelayer exceeds about 20%, it seems that the spaces (voids) between thepowder is beginning to form in the adhesive layer, and the brilliantblue inside the adhesive layer is beginning to be released via thespaces. Also, when the volume of the powder to be added for the adhesivelayer exceeds about 50%, it seems that the spaces (voids) between thepowder are completely formed in the adhesive layer. Thus, we think thatthe additional powder makes no change in the release property of thebrilliant blue.

On the other hand, it was shown that when the volume of the powder to beadded exceeds about 110% of the volume of the adhesive layer, thepreparation becomes hard, and the adhesibility of the preparation isdeteriorated and it is unsuitable for a drug formulation. Thus, it wasdemonstrated that the upper limit of the amount of AEROSIL® to be addedwas about 110%.

Next, CEOLUS® (crystalline cellulose) having a larger bulk density(i.e., having a smaller particle size) than AEROSIL® was used as thepowder, and the effects in various volumes of the powder were evaluated.Specifically, the release property of the brilliant blue from theadhesive layer was evaluated using CEOLUS® as the powder according tothe above Table 2.

TABLE 3 B1 B2 B3 B4 B5 B6 B7 B8 Drug Solution: Brilliant blue 0.0160.016 0.016 0.016 0.016 0.016 0.016 0.016 FCF Triethanolamine 10 9.889.76 9.39 9.15 8.78 9.53 8.17 Levulinate/Macro gol 400 Adhesive:Triethanolamine 10 9.88 9.76 9.39 9.15 8.78 9.53 8.17 Levulinate/Macrogol 400 Terpene Resin 38 37.54 37.07 35.68 34.75 33.36 32.43 31.03 SIS20 19.76 19.51 18.78 18.29 17.56 17.07 16.33 Liquid Parffin 17 16.7916.59 15.96 15.55 14.92 14.51 13.88 Butylhydroxytoluene 1 0.99 0.98 0.980.97 0.96 0.95 0.94 (Total weight of 96.0 94.8 93.7 90.1 87.8 84.3 81.978.4 adhesive layer) Filler (Powder): CEOLUS ® (crystalline 0 1.17 2.355.87 8.21 11.73 14.08 17.6 cellulose) (Volume) (8.4) (16.8) (41.9)(58.6) (83.8) (100.5) (125.7) Volume ratio of 0 8.9 17.9 46.5 66.7 99.4122.7 160.3 powder to adhesive layer (%) Preparation Form: good goodgood good good good good good Emission Amount 0.008 0.017 0.058 0.1250.194 0.213 0.294 0.273 (Absorbance/ Measurement Wavelength 630 nm)[NOTE] The volume of CEOLUS ® was calculated according to the weightthereof/the bulk density thereof. The “volume ratio of the powder to theadhesive layer” was calculated according to the specific gravity of theadhesive layer containing the drug solution defined as 1.

FIG. 3 is a diagram showing the emission amount of brilliant blue FCF asshown in the above Table 3. FIG. 3 shows that when the volume of CEOLUS®to be added for the adhesive layer exceeds about 20%, the emissionamount of brilliant blue is gradually raised. Also, FIG. 3 shows thatwhen the volume of CEOLUS® to be added exceeds about 120% of the volumeof the adhesive layer, the emission amount of brilliant blue reaches apeak.

The difference between the amounts (volumes) of the powder to be addedas shown in the above Table 2 and Table 3 is shown to be influenced bythe difference between the bulk densities of CEOLUS® and AEROSIL®. Thebulk density of AEROSIL® is smaller than that of CEOLUS®, and thus thevolume of the spaces (voids) between the powder becomes larger. As aresult, AEROSIL® in small amount can make the spaces (voids) in theadhesive layer.

In addition, the results of corn starch having a larger bulk densitythan CEOLUS® are shown in Table 4 below and FIG. 4.

TABLE 4 C1 C2 C3 C4 C5 C6 C7 C8 Drug Solution: Brilliant blue 0.0160.016 0.016 0.016 0.016 0.016 0.016 0.016 FCF Triethanolamine 10 9.589.17 7.92 7.09 5.84 5.01 3.77 Levulinate/Macro gol 400 Adhesive:Triethanolamine 10 9.58 9.17 7.92 7.09 5.84 5.01 3.77 Levulinate/Macrogol 400 Terpene Resin 38 36.42 34.84 30.10 26.94 22.21 19.05 14.31 SIS20 19.17 18.34 15.84 14.18 11.69 10.03 7.53 Liquid Parffin 17 16.2915.59 13.47 12.05 9.93 8.52 6.40 Butylhydroxytoluene 1 0.96 0.92 0.790.71 0.58 0.50 0.38 (Total weight of 96.0 92.0 88.0 76.1 68.1 56.1 48.136.2 adhesive layer) Filler (Powder): corn starch 0 3.99 7.98 19.9527.93 39.9 47.88 59.85 (Volume) (8.0) (16.0) (39.9) (55.9) (79.8) (95.8)(119.7) Volume ratio of 0 8.7 18.2 52.4 82.1 142.2 199.2 330.7 powder toadhesive layer (%) Preparation Form: good good good good good bad badbad Amount of Emission 0.012 0.017 0.039 0.092 0.212 0.304 — —(Absorbance/ Measurement Wavelength 630 nm) [NOTE] The volume of cornstarch was calculated according to the weight thereof/the bulk densitythereof. The “volume ratio of the powder to the adhesive layer” wascalculated according to the specific gravity of the adhesive layercontaining the drug solution defined as 1. —: not measured because ofbad preparations.

In order to make the spaces (voids) between the powder in the adhesivelayer by using corn starch having a large bulk density, it was shownthat it is necessary to add a large amount of corn starch. However, whencorn starch was excessively added, it got difficult to formulate thedrug, and thus the measurement of the emission amount of the brilliantblue was discontinued. As a result, the amount of corn starch to beadded for maximizing the emission amount of the brilliant blue could notbe found.

Also, when the volume of the powder was calculated based on the tapdensity of the powder in place of the bulk density of the powder, thecalculated volume became smaller. As a result, as shown in FIG. 5 andFIG. 6, the ratio of [the volume of the powder] to [the volume of theadhesive layer] became smaller, and the value in the horizontal axis wasdecreased.

Thus, the spaces (voids) between the powder formed in the adhesive layerare beginning to be formed by combining the powder when the volume ofthe powder for the volume of the adhesive layer (comprising a drug,etc.) is about 20% (calculated as the bulk density of the powder) asshown in FIG. 2 and FIG. 3. In addition, as shown in FIG. 5 and FIG. 6,the spaces (voids) between the powder are completely formed when thevolume of the powder for the volume of the adhesive layer (comprising adrug, etc.) reached about 60% (calculated as the tap density of thepowder). This result is summarized in the following inequality.

${0.2\mspace{14mu} \left( {{calculated}\mspace{14mu} {as}\mspace{14mu} {the}\mspace{14mu} {bulk}\mspace{14mu} {density}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}} \right)} \leqq \frac{\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}} \right)}{{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {adhesive}\mspace{14mu} {layer}} \leq {0.6\mspace{14mu} \left( {{calculated}\mspace{14mu} {as}\mspace{14mu} {the}\mspace{14mu} {tap}\mspace{14mu} {density}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}} \right)}$

More specifically, when the powder is light anhydrous silicic acid, thevolume of the powder is preferably in the range of 0.2 to 0.6 calculatedas the bulk density thereof, and in the range of 0.1 to 0.3 calculatedas the tap density thereof. Similarly, when the powder is crystallinecellulose, the volume of the powder is preferably in the range of 0.2 to1.2 calculated as the bulk density thereof, and in the range of 0.1 to0.6 calculated as the tap density thereof. In addition, when the powderis corn starch having a large bulk density, the volume of the powder ispreferably in the range of 0.2 to 0.7 calculated as the bulk densitythereof, and in the range of 0.1 to 0.4 calculated as the tap densitythereof. Also, when the volume of the powder in the above inequality isconverted into the amount (weight) of the powder to be added, theinequality is expressed as the following inequality.

0.2×(the weight of the adhesive layer)×(the bulk density of thepowder)≤the amount of the powder to be added≤0.6×(the weight of theadhesive layer)×(the tap density of the powder).

The amount (weight) of the powder to be added can be determineddepending on the total weight of the adhesive layer comprising a drugand a solvent. Thus, when the amount of the ingredients such as thedrug, the elastomer, and the tackifier in the adhesive layer ismaintained at a constant rate, the upper limit and lower limit of thevolume of the solvent available for the adhesive layer can bedetermined. That is, the volume of the solvent to be filled in thespaces (voids) between the powder can be determined. When the volume ofthe solvent exceeds the upper limit, the solvent exudes onto the surfaceof the adhesive layer. As a result, the adhesibility of the tapepreparation to the skin is decreased, and the tape preparation is easilyremoved. Thus, the upper limit of the volume of the solvent to be addeddepends on the amount of the powder to be added.

Example 3 Weight-Composition of Powder and Spaces (Voids) Between PowderFormed in Adhesive Layer (1) Measurement of the Amount of Powder to beAdded Required for Forming Spaces (Voids):

The above results of Example 2 were converted to the weight-compositionof the powder to show the emission amount of brilliant blue FCFgraphically. The results are shown in FIGS. 7 to 9.

The rate of the spaces (voids) between the powder formed in the adhesivelayer was estimated based on the weight-composition (w/w %) of thepowder, and the estimated rate was shown to be greatly affected by thebulk density (tap density) of the powder. Specifically, it wasdemonstrated that light anhydrous silicic acid having a large particlesize and small bulk density of the powder could form the spaces (voids)between the powder in the adhesive layer in a small amount of lightanhydrous silicic acid, whereas crystalline cellulose and corn starchwere required to further increase the amount of the powder to be added,and the spaces (voids) between the powder could not be sufficientlyformed when the weight-composition of the powder (w/w %) was not high.That is, when the amount of powder having a large particle size such aslight anhydrous silicic acid was 1 w/w % or more, the spaces (voids)were beginning to be formed, and when the amount was 2.5 w/w % or more,the spaces (voids) were sufficiently formed. Also, it was shown that theamount of the powder to be added is preferably 5 w/w % or less in viewof the emission amount of the brilliant blue.

In addition, when the amount of crystalline cellulose to be added was2.5 w/w % or more, the spaces (voids) between the powders were beginningto be formed, and when the amount was 15 w/w %, the spaces (voids)between the powders were sufficiently formed. Also, it was shown thatthe amount of the powder to be added is preferably 18 w/w % or less inview of the emission of the brilliant blue.

Thus, it was demonstrated that the amount of the powder to be addedvaries depending on the type of the powder to be added, but thepreferred amount of the powder is in the range of 1 to 18 w/w %. Also,the amount of light anhydrous silicic acid for forming sufficient spaces(voids) is preferably 1 to 5 w/w %, and more preferably 2.5 to 5 w/w %.Also, it was shown that the amount of crystalline cellulose ispreferably 2.5 to 18 w/w %, and more preferably 5 to 15 w/w %.

(2) Measurement of the Amount of Solvent Required for Filling the Spaces(Voids) Formed:

Maintaining the amount of the powder in the adhesive layer (lipophilicadhesive plaster base) at a constant rate and using various solvents, westudied how volume of each solvent is suitable for exuding onto thesurface of the adhesive layer without being held in the spaces (voids)between the powder. When a solvent exudes on the surface of the adhesivelayer, the adhesibility of the adhesive layer is decreased. Thus, theadhesibility of the surface of the adhesive layer was evaluated tocalculate the volume of a solvent held in the spaces (voids) between thepowder.

Each reagent was weighted according to the composition (w/w %) in Table5 below, terpene resin, styrene-isoprene-styrene copolymer (SIS),diethyl sebacate, and liquid paraffin were dissolved in toluenefollowing the conventional solvent method, and then macrogol 400 andlight anhydrous silicic acid (AEROZIL® 200) were added thereto andmixed. Then, each mixture was applied on the silicone-coated PET filmand dried. After removal of the toluene, the backing support waslaminated to prepare each preparation. The ball tack test was performedon the samples to check whether Ball No. 4 was stopped.

The result is shown in Table 5 below.

TABLE 5 Formulation D1 D2 D3 Solvent Macrogol 400 34 41 45 (the volumeof the solvent) (30.6) (36.9) (40.5) Adhesive Terpene Resin 20 20 20Layer Styrene-Isoprene-Styrene 15 15 15 Copolymer Liquid Paraffin 25 1814 3 3 3 Powder Light Anhydrous Silicic 3 3 3 Acid (AEROSIL ® 200)(33.3) (33.3) (33.3) Total 100 100 100 Ratio of the solvent (the drug0.9 1.1 1.2 solution) to the volume of the powder (the amount of thepowder/the tap density of the powder) Ball Tack Test Result on Ball No.4 Stopped Stopped Not Stopped [NOTE] Macrogol 400 specific gravity of1.11

The “Drug approval and licensing procedures in Japan” describes thatpatch preparations have an excellent adhesibility when stopping ball No.4. As shown in the above Table 5, in the ball tack test of FormulationNo. D3, ball No. 4 was not stopped. As a result, the adhesibility of thepreparation was deteriorated. The results show that when the solvent(macrogol) exceeds 1.2 times the volume of the powder, the volume of thesolvent used exceeds the volume capacity of the spaces (voids) betweenthe powder, and the solvent exudes onto the surface of the adhesivelayer.

According to the above results of the ball tack test, it wasdemonstrated that the volume of the spaces (voids) between the powder inthe adhesive layer (lipophilic plaster base material) is smaller than1.2 times the volume of the powder, and the volume is in the range ofabout 1.1 times the volume of the powder. As a result, the upper limitof the amount of the solvent to be added can be determined according tothe following inequality.

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The solvent held in the spaces (voids) in the adhesive layer is asolvent which is hard to dissolve in the adhesive layer (lipophilicplaster base material) (i.e. a solvent which is less compatible with theadhesive layer), and examples of the solvent include an alcohol solvent(e.g. macrogol, propylene glycol, and polyethylene glycol) and a proticsolvent such as a fatty acid-based ionic liquid and a fatty acid. On theother hand, an ester solvent (e.g. diethyl sebacate and isopropylmyristate) is more compatible with the adhesive layer (lipophilicplaster base material), and thus it seems that the solvent is hard to beretained in the spaces (voids) in the adhesive layer.

Example 4 Preparation of Tape Preparations Containing Light AnhydrousSilicic Acid

Following the above results of Example 3, tape preparations comprisingthe powder and agomelatine as an active ingredient were prepared. Eachreagent was weighed according to the composition (w/w %) in Table 6below to prepare the tape preparations by the conventional solventmethod. Table 6 also shows the results on the permeability ofagomelatine in the Franz cell method.

TABLE 6 Test No. A068 A103 A102 A092 A093 A097 A098 Agomelatine 1.0 1.01.0 1.0 1.0 1.0 1.0 (Powder) Light Anhydrous 1.0 2.0 3.0 3.5 4.0 5.0Silicic Acid (Organic Solvent) Isopropyl Myristate 5.0 5.0 5.0 5.0 5.05.0 5.0 Propyl Carbonate 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Polyethylene Glycol5.0 5.0 5.0 5.0 5.0 5.0 5.0 N-Methyl-Pyrrolidone 2.8 2.8 2.8 2.8 2.8 2.82.8 (Fatty Acid-Based Ionic Liquid) Triisopropanolamine 0.9 0.9 0.9 0.90.9 0.9 0.9 Decanoate Diisopropanolamine 1.3 1.3 1.3 1.3 1.3 1.3 1.3Oleate Diisopropanolamine 3.0 3.0 3.0 3.0 3.0 3.0 3.0 IsostearateTriethanolamine 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Lactate (Lipophilic plasterbase) Terpene Resin 38.0 38.0 37.0 36.0 36.0 36.5 36.0 SIS 18.0 17.017.0 17.0 17.0 16.0 16.0 Liquid Paraffin 17.0 17.0 17.0 17.0 16.5 16.516.0 (Antioxidant) Butylhydroxytoluene 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Total100.0 100.0 100.0 100.0 100.0 100.0 100.0 Skin Permeation 51.7 19.1 17.212.8 7.1 9.4 5.0 Amount (μg/cm²/6 hr)

As shown in the above Table 6, the release property of the drug in thetape preparations containing light anhydrous silicic acid had a tendencyto be sustainedly released with increasing the amount of the powder, andthe cumulative skin permeation amount for 6 hours tended to bedecreased. Then, we changed the powder from light anhydrous silicic acidto crystalline cellulose to evaluate the changes in the release propertyof the drug.

Example 5 Preparation of Tape Preparations Containing CrystallineCellulose

In the same manner as Example 4, tape preparations containingcrystalline cellulose as the powder were prepared. Each reagent wasweighed according to the composition (w/w %) in Table 7 below to preparethe tape preparations by the conventional solvent method. Table 7 alsoshows the results about the permeability of agomelatine in the Franzcell method.

TABLE 7 Test No. A068 A104 A105 A106 A107 A108 Agomelatine 1.0 1.0 1.01.0 1.0 1.0 (Powder) Crystalline Cellulose 1.0 2.0 3.0 4.0 5.0 (OrganicSolvent) Isopropyl Myristate 5.0 5.0 5.0 5.0 5.0 5.0 Propyl Carbonate5.0 5.0 5.0 5.0 5.0 5.0 Polyethylene Glycol 5.0 5.0 5.0 5.0 5.0 5.0N-Methyl-Pyrrolidone 2.8 2.8 2.8 2.8 2.8 2.8 (Fatty Acid-Based IonicLiquid) Triisopropanolamine 0.9 0.9 0.9 0.9 0.9 0.9 DecanoateDiisopropanolamine Oleate 1.3 1.3 1.3 1.3 1.3 1.3 Diisopropanolamine 3.03.0 3.0 3.0 3.0 3.0 Isostearate Triethanolamine Lactate 2.0 2.0 2.0 2.02.0 2.0 (Lipophilic plaster base) Terpene Resin 38.0 38.0 37.0 36.0 36.035.0 SIS 18.0 17.0 17.0 17.0 16.5 16.5 Liquid Paraffin 17.0 17.0 17.017.0 16.5 16.5 (Antioxidant) Butylhydroxytoluene 1.0 1.0 1.0 1.0 1.0 1.0Total 100.0 100.0 100.0 100.0 100.0 100.0 Skin Permeation Amount 51.79.4 8.1 6.9 4.9 6.6 (μg/cm²/6 hr)

As shown in the above Table 7, the drug in the tape preparationscontaining crystalline cellulose was more sustainedly released ascompared to the drug in the tape preparation containing light anhydroussilicic acid, and thus the cumulative skin permeation amount for 6 hourswas also more decreased.

The results suggest that the spaces (voids) between the powder were notsufficiently formed in the adhesive layer due to the small amount ofcrystalline cellulose to be added. Specifically, it seemed that it isnecessary to increase the bulk density of the powder to suitably formthe spaces (voids) between the powder. Thus, we tried mixing some typesof powders having different particle sizes to improve the bulk densityof the powder.

It has been known that the volume of a mixture of powders becomes thesmallest when two types of powders having different particle sizes arecombined and the amount of powder having a larger particle size to beadded accounts for about 70% of the total as shown in FIG. 10 (e.g.Kimio KAWAKITA et al., Bulletin of the Faculty of Engineering, HoseiUniversity 2, pages 47-53). Thus, we studied about the combination ofpowders and the release property of the drug based on the abovecomposition.

Example 6 Preparation of Tape Preparation Containing Light AnhydrousSilicic Acid and Crystalline Cellulose

Light anhydrous silicic acid (having a larger particle size) andcrystalline cellulose (having a smaller particle size) were used as thepowder having different particle sizes to prepare tape preparationscontaining powder according to the composition (w/w %) in Table 8 below.Table 8 also shows the results about the permeability of agomelatine inthe Franz cell method.

TABLE 8 Test No. A068 A082 A085 A088 Agomelatine 1.0 1.0 1.0 1.0(Powder) Light Anhydrous Silicic Acid 3.0 2.0 1.0 Crystalline Cellulose3.0 3.0 3.0 (Organic Solvent) Isopropyl Myristate 5.0 5.0 5.0 5.0 PropylCarbonate 5.0 4.0 4.0 4.5 Polyethylene Glycol 5.0 4.0 4.0 4.5N-Methyl-Pyrrolidone 2.8 0.8 0.8 (Fatty Acid-Based Ionic Liquid)Triisopropanolamine Decanoate 0.9 0.9 0.9 0.9 Diisopropanolamine Oleate1.3 1.3 1.3 1.3 Diisopropanolamine Isostearate 3.0 3.0 3.0 3.0Triethanolamine Lactate 2.0 2.0 2.0 2.0 (Lipophilic plaster base)Terpene Resin 38.0 36.0 35.0 35.0 SIS 18.0 17.0 17.0 17.0 LiquidParaffin 17.0 17.8 19.0 19.0 Polybutene 1.0 1.0 1.0 (Antioxidant)Butylhydroxytoluene 1.0 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0 SkinPermeation Amount 51.7 12.2 11.7 45.1 (μg/cm²/6 hr)

As shown in the above Table 8, when light anhydrous silicic acid (havinga larger particle size) and crystalline cellulose (having a smallerparticle size) were combined at a weight ratio of 1:3, the releaseproperty of the drug was unexpectedly and drastically improved. Theresult was obtained when the amount of light anhydrous silicic acidhaving a larger particle size was 25%. FIG. 10 shows that the bulkdensity of the mixture can reach a peak when the amount of lightanhydrous silicic acid to be added is 70%. However, the result wasagainst the theory, which showed that 70 to 80% crystalline cellulosewas necessary to suitably form the spaces (voids) in the adhesive layerbetween the mixed powders. As described above, it was found that it ispreferable in case of mixed powders to mix powder having a smallerparticle size and powder having a larger particle size at a ratio of 70to 80:20 to 30 to effectively form the spaces (voids) in the adhesivelayer. As a result, the drug solution can be retained in the spaces(voids) of the adhesive layer or the drug solution can be transferred tothe surface of the tape preparation via the spaces (voids), and thus thedrug solution or the drug can be released from the surface of the tapepreparation.

Example 7

Evaluation of the Release Property of Drug with Adhesive LayerContaining Powder

The above results of Example 6 suggest that when two types of powders(fillers) having different particle sizes are added into the adhesivelayer of the tape preparations, the drug solution containing the drug(agomelatine) can be retained in the spaces (voids) between the powder(filler) or between the powder and the adhesive layer, and also the drugsolution or the drug within the adhesive layer can be effectivelyreleased onto the surface of the adhesive layer via the spaces. As aresult, it was shown that the ratio of the residual drug in the adhesivelayer was much lower than that of the conventional tape preparations.

The tape preparations were prepared according to the composition (w/w %)in Table 9 below, and the change in the drug blood level in mice wasmeasured to verify the above effect of the present invention.Specifically, the tape preparations were prepared according to themethod of Example 2. The tape preparations were used for evaluating thetransdermal absorbability of the drug in the Franz cell method of TestExample 1 and the change in the drug blood level in mice. The resultsare shown in Table 9 and FIG. 11.

TABLE 9 Test No. A260 A244 Agomelatine 2.0 2.0 (Powder) CrystallineCellulose 3.0 Light Anhydrous Silicic Acid 1.0 (Organic Solvent)Dimethylisosorbide 1.2 1.2 Isopropyl Myristate 5.7 5.7 Propyl Carbonate5.0 5.0 Polyethylene Glycol 7.5 7.5 (Fatty Acid-Based Ionic Liquid)Triethanolamine Isostearate 2.5 2.5 Triethanolamine Lactate 1.5 1.5(Lipophilic plaster base) SIS 17.2 16.5 Terpene Resin 35.0 33.7 LiquidParaffin 19.5 17.5 (Other Additives) Butylhydroxytoluene 1.0 1.0 Total100.0 100.0 Cumulative Skin Permeation 6.2 36.5 Amount at 6 hours(μg/cm²)

As shown in Table 9, comparing the preparation of Test No. A260 ofhaving the adhesive layer with no powder with the preparation of TestNo. A244 having the adhesive layer containing the powders, thetransdermal absorbability of the drug in the tape preparation containingthe powders was dramatically improved. Specifically, it was shown thatthe transdermal absorbability of the drug in the preparation containingthe powders was improved by about 6 times as compared to that of thetape preparation with no powder. This means that the release of the drugfrom the adhesive layer was increased by about 6 times. Thus, it seemsthat the drug was easily released from the surface of the adhesive layervia the spaces (voids) formed by the addition of the powders to theadhesive layer.

In addition, it has been found that when in vivo drug blood level inmice was evaluated according to Test Example 1, the preparationcontaining the powders (Test No. A244) sustainedly released the drug asshown in FIG. 11.

The preparation of Example 6 with no powder (Test No. A068) was shown tohave the excellent transdermal absorbability of the drug. As shown inFIG. 12, however, the change in the drug blood level was evaluated witha rat treated with (Test No. A068), in which the drug blood levelreached a peak 2 hours after the preparation was applied to the skin,and then was rapidly decreased. The change in the drug blood level asshown in FIG. 12 is greatly different from that of the present inventionas shown in FIG. 11.

FIG. 13 shows that the change in the drug blood level of the presentinvention as shown in FIG. 11 is composed of biphasic behaviors of adashed part showing immediate-release property of the drug and a dottedpart showing the slow-release property of the drug. As shown in FIG. 14,these behaviors are derived from the presence of the region forming thespaces (voids) in which the powders are collectively combined in theadhesive layer and the region in which the powder is relatively empty inthe adhesive layer, that is, the region in which the spaces (voids) arenot sufficiently formed.

As described above, the release property of the drug from the adhesivelayer containing the powder of the present invention is composed of thebiphasic properties (immediate-release and sustained-release properties)as shown in FIG. 13. Thus, it has been found that it is possible to makeany one selected from the immediate-release and sustained-releasebehaviors of the drug better by arranging the amount of the powders tobe added and the combination of the powders.

Example 9

Evaluation of the Utilization Rate of Drug in Tape Preparations withAdhesive Layer Containing Powder (1) Tape Preparation ComprisingAgomelatine as Active Ingredient

In the same manner as Example 2, each reagent was weighed according tothe composition (part by weight) in Table 10 below to prepare the tapepreparations comprising agomelatine as a drug.

Specifically, agomelatine was mixed with the fatty acid-based ionicliquids to prepare a drug solution. Following the conventional solventmethod using toluene as the solvent, the organic solvents, theantioxidants, the lipophilic plaster base materials, and the drugsolution were mixed. Next, crystalline cellulose and light anhydroussilicic acid were added thereto and mixed, and then the mixture wasapplied on the silicone-coated PET film and dried. After removal of thetoluene, the backing support was laminated to prepare the preparation.

Following Test Example 1 below, the in vitro skin permeability test wasperformed with the prepared patch preparations comprising agomelatine.The results are also shown in Table 10.

TABLE 10 Test No. A223 A197 Agomelatine 1.0 1.0 (Powder) Light AnhydrousSilicic Acid 1.0 Crystalline Cellulose 3.0 (Organic Solvent) IsopropylMyristate 3.8 3.8 Propyl Carbonate 6.0 5.0 Polyethylene Glycol 6.0 5.0(Fatty Acid-Based Ionic Liquid) Triethanolamine Isostearate 2.5 2.5Triethanolamine Lactate 1.5 1.5 (Lipophilic plaster base) Terpene Resin36.3 35.3 Styrene-Isoprene-Styrene Block 20.0 19.0 Copolymer LiquidParaffin 19.5 19.5 (Other Additives) Kollidon ® K90 0.5 0.5 Oleic Acid1.9 1.9 Butylhydroxytoluene 1.0 1.0 Total Skin Permeation Amount 9.126.7 (μg/cm²/6 hr)

As shown in Test Nos. A197 and A223 of the above Table 10, thetransdermal absorbability of agomelatine in the tape preparationcontaining the powders was improved by about 3 times.

In addition, the measured ratio of the residual drug in the preparationof Test No. A197 was about 40%. As a result, it was found that the ratioof trandermally-absorbed agomelatine was about 60%. Thus, it was shownthat the tape preparation of the present invention containing powderproduced the excellent effect that the drug was transdermally absorbedat a high utilization rate.

(2) Tape Preparations Comprising Oxycodone as Active Ingredient

In the same manner as Example 2, each reagent was weighed according tothe composition (part by weight) in Table 11 below to prepare the tapepreparations comprising oxycodone as a drug.

Specifically, oxycodone hydrochloride hydrate was mixed with the fattyacid-based ionic liquids to prepare a drug solution. Following theconventional solvent method using toluene as the solvent, organicsolvents, antioxidants, lipophilic plaster base materials, lightanhydrous silicic acid, and the drug solution were mixed, and then eachmixture was applied on the silicone-coated PET film and dried. Afterremoval of the toluene, the backing support was laminated to prepare thepreparations.

Following Test Example 1 below, the in vitro skin permeability test wasperformed with the prepared patch preparations comprising oxycodone. Theresults are also shown in Table 11.

TABLE 11 Test No. K886 K884 N423 Oxycodone Hydrochloride 2.31 2.31 2.31Hydrate (Powder) Light Anhydrous Silicic Acid 4.0 4.0 (Organic Solvent)Isopropyl Myristate 5.0 5.0 5.0 Propyl Carbonate 10.0 10.0 10.0Propylene Glycol 14.5 14.5 Dipropylene Glycol 5.0 Oleyl Alcohol 5.0Diethyl Sebacate 7.0 (Fatty Acid-Based Ionic Liquid + Fatty Acid) CapricAcid 0.98 0.98 0.98 Isostearic Acid 6.0 6.0 6.0 Myristic Acid 0.4 0.40.4 Oleic Acid 0.8 0.8 0.8 Diisopropanolamine 1.65 1.65 1.98 (Lipophilicplaster base) Terpene Resin 27.0 27.0 30.0 Plastibase ® 5.0 5.0Styrene-Isoprene-Styrene 15.0 15.0 16.0 Block Copolymer Liquid Paraffin3.27 3.27 4.54 (Other Additives) Butylhydroxytoluene 1.0 1.0 1.0Ascorbic Acid 0.1 0.1 0.1 Sodium Lactate 0.9 Total 96.0 100.0 100.0 SkinPermeation Amount 122 160 89 (μg/cm²/6 hr) Adhesibility Test 2 37 —(Ball Tack Test) (difficulty (stopp- Adhesion Time of Ball in ing) No. 4(sec) stopping) Ratio of the residual drug (%) — 15 19 [NOTE] — Notmeasured

As shown in the above Table 11, the tape preparation with no powder(Test No. K886) contains a large volume of the solvent, and thus thesolvent exudes onto the surface of the adhesive layer. As a result, theadhesibility of the tape preparation is not strong. On the other hand,the preparation containing the powder (Test No. K884) which has the samecomposition as the tape preparation with no powder (Test No. K886) wasimproved in the transdermal absorbability of the drug by 1.3 times. And,the adhesibility of the tape preparation was also increased. Inaddition, the ratio of the residual drug in the tape preparationcontaining the powder was about 15%, and thus it is presumed that theratio of the transdermally-absorbed drug was about 85%.

As described above, the composition for the tape preparation containingthe powder was improved in the transdermal absorbability of the drug,and the utilization rate of the drug was dramatically improved. Theutilization rate of the drug in conventional tape preparations isgenerally about 10%, whereas the utilization rate of the drug in thetape preparations containing the powder (Test No. K884 and Test No.N423) was more than 80%, said high utilization rate of the drug was anexcellent result. In addition, it was shown that the adhesibility of thetape preparations containing the powder was also effectively maintainedby comparison of the preparations of Test No. K886 and Test No. 884.

The preparation of Test No. N423 is a tape preparation in which theamount of the powder to be added is decreased and the relative amount ofthe ester solvent is increased as compared to the preparation of TestNo. K884. On the other hand, the skin permeation amount of thepreparation of Test No. N423 in Table 11 was decreased by about half ascompared to that of the preparation of Test No. K884, but the ratio ofthe residual drug was 19%, i.e., the ratio of the residual drug showedlittle change. The drug blood level was measured according to TestExample 2. The result showed that the drug blood level reached a peakabout 3 hours after the preparation was applied to the skin as shown inTable 12 below and FIG. 15.

TABLE 12 0 hr 3 hr 8 hr 24 hr Drug Blood level (ng/mL) 0 54.5 16.5 0Ratio of the residual drug (%) 19

The volume of the powder in the preparation of Test No. N423 (33.3 ml in100 g of the preparation) is thought to be close to that of the solventwhich is less compatible with the powder such as an alcohol solvent anda fatty acid-based ionic liquid. From the result, we think thatoxycodone can be easily released as shown in Table 12 and FIG. 15. Thus,the image in FIG. 14 is supported by the change in the drug blood level.

Test Example 1 In Vitro Skin Permeability Test

The tests for evaluating the transdermal absorbability of agomelatine inthe tape preparations of Examples 4 to 9 were performed using a Franzdiffusion cell (the permeable area: 1 cm², the volume of the receptorsolution: 8 mL) at a test temperature of 32° C. as follows:

(1) Rat's skin: skin isolated from the abdomen of a 5-week old Wistarrat (male)(2) Receptor solution: physiological saline+10% ethanol(3) Concentration measurement of the permeable drug: HPLC

The commercially available rat's abdominal frozen skin (5-week oldWistar rat) was mounted in a vertical diffusion cell (the effectivediffusion area: 1 cm²). Each sample in Tables 5 to 11 was applied to thestratum corneum side, and physiological saline+10% ethanol was appliedto the dermic layer side. The skin permeability of the drug was measuredby HPLC to determine the cumulative permeation amount of the drug for 2hours and 4 hours. As a result, the transdermal absorbability ofagomelatine as shown in Tables 5 to 11 could be evaluated.

Test Example 2 Test for Evaluating In Vivo Drug Blood Levels in Rats (1)Laboratory Animal:

5-week old Wistar rat (male)

(2) Test Method:

The test sample was prepared by cutting the preparation sample of TestNo. A068 (agomelatine, 133 μg/cm²) into 2 cm×2 cm as an adhesive plastertype patch preparation. One group was composed of 6 rats. The hairsaround the administration site (from the back to the lateral region) onthe rats were removed with an electric hair clipper [THRIVE, Model 5500(0.05 mm), Daito Electric Machine Industry Co., Ltd.], and then thewhiskers on the rats was removed with an electric shaver (Cleancut,Seiko S-Yard Co. Ltd.). To each rat were attached 3 sheets of thepreparation samples, and blood was collected from the rats 1 hour, 2hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration.

To glass tubes were added 200 μl of the blood plasma collected from therats, and 200 μl of physiological saline was added thereto and theplasma was homogenized. Then, 500 μl of diethyl ether was added thereto,and each mixture was stirred with a vortex mixer, and then centrifugedfor 10 minutes to collect the ether layer. Similar ether extractionmethod was performed on the remaining water layer 3 times in total. Theextracted ether layer was combined, and the solvent in the combinedether layer was distilled away under high purity nitrogen stream. Afterevaporation of the ether, 200 μl of water was added to the resultingdried residues to dissolve the residues. Then, each solution was passedthrough a 0.45 μm filter for filtration, and 10 μl of the filtrate wasanalyzed by HPLC.

Also, the preparation sample of Test No. A244 (agomelatine, 266 μg/cm²)was prepared to measure the drug blood levels in the rats in the samemanner as the above.

As with the above, using oxycodone, the drug blood levels in the ratswere measured (oxycodone hydrochloride, 286 μg/cm²). The preparation ofTest No. N423 was used as the sample.

(3) Results

FIG. 11 and FIG. 12 show the changes in the level of agomelatine in theplasma obtained from the above analyzed results. In addition, FIG. 15shows the change in the level of oxycodone in the plasma.

INDUSTRIAL APPLICABILITY

The non-aqueous tape preparation of the present invention comprisingpowder ingredient is characterized in that the powder ingredient makesspaces in a lipophilic adhesive layer, a drug solution is retained inthe spaces, and then a drug is gradually released. Also, the tapepreparation has an improved adhesibility since a solvent is not retainedonto the surface of the adhesive layer of the tape preparation. Inaddition, both of the adhesibility of the tape preparation and therelease property of the drug solution, which are conflicting factors innormal tape preparations, can be improved in the present invention, andthus the transdermal absorbability of the drug can also be improved.Thus, the tape preparation of the present invention has an excellentadhesibility to the skin and further an improved transdermalabsorbability of the drug, based on the above effects. Also, the tapepreparation can sustainedly release the drug since the drug solution isgradually released from the spaces between the powder. As a result, thenon-aqueous tape preparation of the present invention has made itpossible to expand the use to new applications in the tape preparationcomprising a drug solution in which a drug is dissolved in an organicsolvent with high polarity or the non-aqueous tape preparationcomprising an ionic liquid, and thus has also made it possible to expandthe possibility of treating diseases with the tape preparation.

1. A composition for a non-aqueous patch preparation comprising a drug,an organic solvent, and a powder which is insoluble both in the organicsolvent and in a lipophilic plaster base material, wherein the powderfor an adhesive layer is contained as shown in the following inequality:0.2×(the weight of the adhesive layer)×(the bulk density of thepowder)≤the amount of the powder to be added≤0.6×(the weight of theadhesive layer)×(the tap density of the powder).
 2. The compositionaccording to claim 1, wherein the powder is at least one selected fromthe group consisting of crystalline cellulose, anhydrous silicic acid,starch, carmellose, carmellose metal salt, kaolin, agar, carrageenan,pectin, and powdered sugar.
 3. The composition according to claim 1 or2, wherein the powder is a mixture of powders.
 4. The compositionaccording to any one of claims 1 to 3, wherein the organic solventcomprises a fatty acid-based ionic liquid and/or a salicylic acid-basedionic liquid.
 5. The composition according to claim 4, wherein the fattyacid-based ionic liquid is an equimolar salt of a saturated orunsaturated fatty acid having 3 to 22 carbon atoms and an alkanolaminehaving 6 to 9 carbon atoms.
 6. The composition according to claim 4 or 5further comprising a saturated or unsaturated fatty acid having 10 to 22carbon atoms.
 7. The composition according to claim 6, wherein thesaturated or unsaturated fatty acid having 3 to 22 carbon atoms is atleast one selected from the group consisting of lactic acid, levulinicacid, decanoic acid, oleic acid, isostearic acid, and myristic acid. 8.The composition according to claim 5, wherein the alkanolamine is atleast one selected from the group consisting of triethanolamine,triisopropanolamine, and diisopropanolamine.
 9. The compositionaccording to claim 5, wherein the fatty acid-based ionic liquid and/orthe salicylic acid-based ionic liquid are at least one selected from thegroup consisting of triethanolamine lactate, triisopropanolaminelactate, triethanolamine levulinate, diisopropanolamine levulinate,triisopropanolamine decanoate, triethanolamine salicylate,diisopropanolamine oleate, triethanolamine isostearate,diisopropanolamine isostearate, and diisopropanolamine myristate. 10.The composition according to any one of claims 1 to 9, wherein thelipophilic plaster base material comprises an elastomericstyrene-isoprene-styrene block copolymer.
 11. The composition accordingto any one of claims 1 to 10, wherein the drug is selected from a smallmolecular medicinal compound, a protein medicine, an antigen peptide, ora nucleic acid derivative.
 12. The composition according to any one ofclaims 1 to 11, wherein the organic solvent is contained as shown in thefollowing inequality: $\begin{matrix}{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {solvent}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix} < {\frac{{the}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}}{\begin{matrix}{{the}\mspace{14mu} {tap}\mspace{14mu} {density}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}} \\\left( {{the}\mspace{14mu} {volume}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {powder}\mspace{14mu} {to}\mspace{14mu} {be}\mspace{14mu} {added}} \right)\end{matrix}} \times 1.2}$